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I teach an intro biology course on viruses at Vassar College. We do our introductory biology a little bit differently; each class has a theme through which we explore the fundamental principles of biology. Mine is on viruses and their hosts, its a great way to explore everything in biology (cells, genetics, evolution etc) and get students hooked on virology in their freshman year.

We had a recent discussion in class on the evolutionary benefits of lysogeny, specifically relating to the temperate phage CTX-phi, which expresses the cholera toxin responsible for the severe diarrhea seen in cholera. The students wondered why not just stick with the lytic cycle, when you can potentially infect so many more cells? What is the benefit of being able to make that switch?

We had also discussed the balance of virulence and transmission, that viruses will evolve towards an appropriate level of virulence based on their mode of transmission (among other factors). So here is an explanation I came up with:

You can think of the lytic cycle as highly virulent (100% mortality, since infected cells will lyse and die) or lysogenic as non-virulent (no negative effect on the host while the phage is present as a prophage). So when would high virulence be favored for transmission and when would low virulence be favored? A highly virulent pathogen runs the risk of wiping out its host population. If the cells are growing actively in an environment like the gut, and the virus is replicating to high levels, it could spread to the entire host population eventually killing every cell. (Viral replication is much faster than cell division and when cells divide, only two cells are made but when viruses replicate, 10s of virions are made.) The virus would then depend on either more V. cholera entering the gut, or getting out of the gut and spreading to a new human host infected with cholera. Alternatively, cholera can also grow in the environment, so the phage could infect a cell in the environment. However there is some obvious risk there, that of finding the next host cholera cell either in a gut or the environment. Its a big world out there for a tiny phage and a tiny bacterial cell to meet each other. A less risky approach might be to limit virulence and allow prophage infected cells to survive. The cholera cells will be returned to the environment, where they can replicate or to a new human host where it can also replicate. Either way, the phage is guaranteed to find a host, because its already in it.

Now if the prophage finds itself in cells that are no longer growing, there may be an advantage to getting out and finding "happy" hosts. Cells that are not growing could be at greater risk of cell damage and death, perhaps they are not acquiring the nutrients and energy necessary to grow or repair cellular damage. If the cell dies, the phage will not be able to replicate. So the phage would enter the lytic cycle and release progeny. The risk of not finding a new host would presumably be lower than the risk of staying within a dying host. High virulence therefore is advantageous for transmission in this situation.

What are your thoughts on this explanation? Im sure there are other ideas and Id be interested in hearing them.

I thought that your readers and listerners would be interested in this.

The following is a link to an article (free access) in the British Medical Journal (published 5/1/11) detailing the story behind how the MMR vaccine-autism paper was forged.

I recommend that you read it and forward it on to as many people as you can, because many people still believe that the conclusions from this paper are true (i.e. vaccines cause autism) even though the original paper has been retracted and the PI (Mr Andrew Wakefield) has been sued for fraud and had his medical licence revoked by the British Medical Association.

I would post a link to the original Wakefield article but it is behind a paywall.

In the first part of a special BMJ series, Brian Deer exposes the bogus data behind claims that launched a worldwide scare over the measles, mumps, and rubella vaccine, and reveals how the appearance of a link with autism was manufactured at a London medical school.

Thanks,

Jacob

Kathy writes:

Hi guys,

I saw this and immediately had to take a picture. Another way of thinking about the cold chain!

Thanks for the recent mention when Rich used my suggestion for Weekly science pick - the story about the grade school children's research about bee behavior! I've now had my 15 seconds of fame ;-)

Cheers,

Kathy

Jim writes:

Two references; the first from Slashdot (http://www.google.com/reader/view/?hl=en&tab=wy#stream/feed%2Fhttp%3A%2F%2Fslashdot.org%2Findex.rss)

has this intro:

"The Logical Leap: Induction In Physics

from Slashdot by samzenpus

FrederickSeiler writes "When David Harriman, this book's author, was studying physics at Berkeley, he noticed an interesting contrast: 'In my physics lab course, I learned how to determine the atomic structure of crystals by means of x-ray diffraction and how to identify subatomic particles by analyzing bubble-chamber photographs. In my philosophy of science course, on the other hand, I was taught by a world-renowned professor (Paul Feyerabend) that there is no such thing as scientific method and that physicists have no better claim to knowledge than voodoo priests. I knew little about epistemology [the philosophy of knowledge] at the time, but I could not help noticing that it was the physicists, not the voodoo priests, who had made possible the life-promoting technology we enjoy today.' Harriman noticed the enormous gulf between science as it is successfully practiced and science as is it described by post-Kantian philosophers such as Feyerabend, who are totally unable to explain the spectacular achievements of modern science."

And all that makes me think we'd be better off telling students they need to research anything they wish, but they have to apply certain rules as they do it. Isn't that what's done for graduate work in England that doesn't require all the American testing, but uses mentor evaluations and a final oral exam?

"All secondary school students should be required to be trained in cardiopulmonary resuscitation (CPR) and receive an overview of automated external defibrillators (AEDs), according to an American Heart Association science advisory."

And that reminded me that while we have loads of word problems, I don't know if we yet are including examples that deal with daily situations (CPR-like) concerned with balancing check books, student loan size versus projected salary size, income tax preparation, or buying that car Vince mentioned at different purchases rates.

No solutions; just meandering thoughts...

Jim

Smithfield, VA

Kathy writes:

Hi guys,

I think it was on #115 where Vincent made a comment about defensins and viruses. There has been some work on that, at least in adenoviruses. A new assistant professor, Jason Smith, at UW in Seattle is continuing work he began as a postdoc with Glen Nemerow. Here's a screenshot of a PubMed search I did. (I half expected Alan to do the search during the show...). (There are a lot more hits if you don't limit it to "smith".)

I enjoyed the discussion about the paper on colored pseudorabies virus from Lynn Enquist's lab. Now I'll have to read it (the first time), then listen again with paper in hand, and maybe read it several more times (from what Rich says)!

I listened to your influences in science while shoveling my driveway (jealous, Rich?!). One of my influences in science (beyond my parents [chemists] and teachers/advisors/mentors) was reading at a young age my father's copy of a translation of the biography of Marie Curie written by her daughter Eve in 1937.

Cheers,

Kathy

Sara writes:

Hi gentlemen,

I discovered the podcast relatively recently and really enjoy your work. I did my undergrad in microbiology and some grad school in public health, and after working for several years as a technician/analyst doing molecular biology and other techniques in academic labs and a vaccine biotech, I just started nursing school.

My goal is to not leave the mentality or love of basic science research behind, and to that end I recently attended a seminar on campus by Paul Goepfert of U Alabama Birmingham with the title: Cryptic Epitopes: Implications for HIV Vaccine Design. The closest-related paper I could find of his with a brief search was published on 18Jan10 in Journal of Experimental Medicine (Pubmed abstract).

I'm not an HIV expert by any means but am fascinated by the challenges this virus poses in practice, namely vaccine development and mutations that lead to multiple drug resistance. (Never mind all the ways human behavior can affect the trajectory of HIV infection, e.g. adherence to ART!)

In this talk, Goepfort honed in on a realization that some HIV vaccines being tested in the field attempt to raise an immune response to epitopes whose sequences have been codon optimized for optimal expression in humans. This is in contrast to other clinical studies using non-codon optimized sequences derived from known field isolates of HIV. The problem with this codon optimization strategy is that the population of immunogenic epitopes from all the other reading frames (2 forward and 3 reverse) is completely different than what the "wildtype" epitope population would look like. If I understand the consequences right, this would mean that even if the vaccine material is expressed well in the patient, the immune response would be largely irrelevant and unprotective (at best).

Is it just me or does the use of codon optimization of a HIV antigen sequence for vaccine use seem like a big "DUH" bad idea in hindsight, because of this issue of the alternative reading frame antigens?

I am aware of vaccine development programs for other viruses, e.g. HSV, that also use codon optimization in the antigen sequence. Would this issue of raising an immune response to antigens expressed from codon optimized sequences cause a similar problem with other vaccine programs? Do all viruses or just retroviruses produce these black box proteins from alternative reading frames? Could the changes resulting from codon optimization also be affecting the effective immunogenicity of vaccines being tested for viruses other than HIV? What are the implications of these unconventional alternative reading frame epitopes in vaccine development? Is this phenomenon studied very often in terms of trying to understand what the ARF proteins made by viruses do in the first place?

This may not be a TWiV appropriate discussion, but I thought it was a riveting real world issue at the junction of the wily behavior of a virus, what that means for individual patients' disease processes, and the expenditures of vast amounts of resources on clinical trials.

Thanks very much for such an accessible, enjoyable, and educational podcast!

Sarah

BSN/RN student, Duke University

BS Microbiology '03 NCSU

Name witheld writes:

I am interested in understanding the means by which XMRV or MLV is 'transmitted'. Is it transmitted by way of vaccination development and becomes operative when a person's immune system is suppressed for whatever reason? As yet I've not seen any article which addresses this issue.

Please note I am an interested private individual. I am not associated with any particular organization etc.

Charles writes:

Hi TWiV Team,

I thought you might find this video entertaining if you have not already seen it. I'm sure some of your followers might enjoy it also. It is a Lady Gaga parody about a bad lab project.

I think in the past I've heard you read emails with "picks of the week". If so, please consider the following book: Denialism by Michael Specter. Have you read it? there is also a short TED talk which touches on the main themes but is too short to convey everything in the book, of course.

Anyway he touches on a lot of the recurring issues that you do in the podcast including the need for more scientific literacy in the general public, the vaccine/autism debacle, poor flu vaccine uptake rates, etc.

Two of my favorite recent quotes have come from Mr. Specter; one from the TED talk ("we leap into the arms of big placebo", and from the last chapter of the book, "Experts chosen to represent a specific point of view are cheerleaders, not scientists. And people who rely on them are denialists."

I highly recommend it.

Neil

John writes:

Dear Doctors,

First some context. My status as a science fan (layperson) goes hand-in-hand with my passion for skepticism. In that regard Carl Sagan would be my intellectual hero in both fields.

So I thought about writing in to give some general comments on the episode partway through. I wanted to express my general disappointment in science communication these days and simultaneously praise efforts like yours to communicate science. When you were talking about what can we (scientists) do to better inform people (decisions based on science vs emotion) I was thinking "well you're already doing it". As a skeptic we encounter this problem on a regular basis. The situation that your guest Mr. Mnookin was describing is a regular occurrence in all areas of woo and pseudoscience. This often arises from the use of a 'token skeptic'. A perfect example of how the media gets it wrong is the recent astrology news. I watched CNN report that the zodiac was changing and therefore your horoscopes might be wrong then juxtaposed it with some random astrologers saying don't worry we know about it already. They all missed the real story which is "why does such a large proportion of the population of an industrialized country believe in magic?". So I would like to add on my toned down reaction which is we need scientists both great and small to become public intellectuals in their spare time. The more they discuss the merits of recent research in their fields the better laypeople are able to understand and be critically skeptical of new stories. Sadly I do not have the patience of wiser men and women and so when I hear about things like jenny mccarthy vs 100,000 doctors it makes me quite angry. Which leads to my next general comment.

I can't believe one of your listeners could be that dense, so willfully ignorant, as to be deifying the likes of andrew wakefield. I understand your show is an educational show about science and rightly eschews emotional reactions and political commentary. Your comment that the fellow's emails "did not reflect that" was perhaps the most diplomatic thing I've heard in a long time. I wish that we as a nation could critically look at the evidence, conclude that this person was a repugnant, morally bankrupt fraud willing to put the lives of children in danger to make a quick buck, exile him to the arctic circle and move on with our collective lives. Once again my background as a skeptic makes me intimately familiar with the arguments used by the anti-vaccine crowd. Whether via cum hoc ergo propter hoc fallacies or their ability to move goalposts faster than the Army Corps of Engineers they spread ignorance and paranoia like the plague. Sadly their 'follow the money' arguments do not trigger any ironic neurons in their brains and prompt them to check on the monetary incentives that wakefield had.

Ranting aside, this all goes to the overarching theme of the episode, in my eyes, which is 'the failure of the scientific community to effectively communicate to the public'. I am perhaps framing the problem unfairly and should add 'and the failure of -insert here- to produce a nation of critical thinkers'. One of the reasons that I like your show and similar groups of scientists discussing science is that I get to hear respectful critical thinking in action. I know it's not virology but part of the show is the communication of science and its role in the public (you aren't keeping Alan Dove around just for his jokes are you?) so given the wakefield debacle perhaps it would be useful to discuss science in the public discourse, what young scientists can do, what science fans can do, kindly urge us to be patient or spur us to action.

So thanks for being my psychiatrists today in addition to my virologists (and parasitologist) while I rant.

Best regards, fan of the show, keep up the good work, lame joke about Alan, shake fist at Rich while it's -2 degrees out, and looking forward to more.